8 19-epoxy-delta 4 6-3-ketosteroids and intermediates for their synthesis

ABSTRACT

DISCLOSED HEREIN ARE THE 8,19-EPOXYSTEROIDS 8,19-EPOXYANDROSTA - 4,6 -DIENE - 3,17 -DIONE, 8,19 - EPOXY - 17BHYDROXYANDROSTA - 4,6 - DIEN - 3 - ONE AND THE 17 - LOWER ACYL ESTERS OF THE LATTER COMPOUND. THE COMPOUNDS ARE USEFUL FOR LOWERING CHOLESTEROL CONCENTRATIONS IN THE BLOOD SERUM AND INHIBITING GONADOTROPHIN SECRETION. METHODS FOR THE PREPARATION AND USE OF THESE 8,19-EXPOXYSTEROIDS ARE GIVEN.

United States Patent O 3,637,667 8,19-EPOXY-A -S-KETOSTEROIDS AND INTER- MEDIATES FOR THEIR SYNTHESIS Gunther Kruger, St. Laurent, Quebec, Canada, assignor to American Home Products Corporation, New York,

Nb brawin Filed Feb. 10, 1970, Ser. No. 10,307 rm. c1. C07c 173/00 US. Cl. 260239.55 10 Claims ABSTRACT OF THE DISCLOSURE Disclosed herein are the 8,19-epoxysteroids, 8,19-epoxyandrosta 4,6 diene 3,17 dione, 8,19 epoxy 17phydroxyandrosta 4,6 dien 3 one and the 17 lower acyl esters of the latter compound. The compounds are useful for lowering cholesterol concentrations in the blood serum and inhibiting gonadotrophin secretion. Methods for the preparation and use of these 8,19-epoxysteroids are given.

BACKGROUND OF THE INVENTION This invention relates to new 8,19-epoxysteroids, to processes used for their synthesis and to intermediates used in these processes.

The 8,19-epoxysteroids of this invention have been found to possess useful pharmacologic properties, such as lowering the cholesterol concentrations in the blood serum and inhibiting gonadotrophin secretion without eliciting undesirable side effects. These properties render the 8,l9 epoxysteroids of this invention useful agents for treating such condtions as hypercholesterolemia and the menopausal syndrome, respectively.

SUMMARY OF THE INVENTION The 8,19-epoxysteroids of this invention may be represented by the following general Formula E:

in which R and R together represent a ketonic oxygen or R represents hydrogen and R represents hydroxyl or lower acyloxy.

DETAILS OF THE INVENTION The 8,19-epoxysteroids of this invention have been found to possess interesting pharmacological properties. More particularly, these compounds, in standard pharmacological tests, for example, in a procedure similar to that described by M. Kraml et =al., J. Med. Chem., 7, 500 (1964) for the testing of agents affecting cholesterol concentrations in the blood serum, have exhibited activities as cholesterol lowering agents.

When the compounds of this invention are employed as cholesterol lowering agents in warm-blooded animals, e.g., in rats, alone or in combination with pharmacologically acceptable carriers, the dosage of the compounds and the proportion of carriers is determined by the solubility and chemical nature of the compound, by the chosen route of administration and by standard biological practice. For example, the compounds may be administered orally in solid form containing such excipients as starch, lactose, certain types of clay, lubricants such as magnesium stearate, and similar ingredients. They may also be administered orally in the form of solutions, or they may be ice injected parenterally. For parenteral administration the compounds of this invention may be administered in the form of sterile solutions containing other solutes, for example, sodium chloride or glucose to make the solution isotonic.

The dosage of the compounds of this invention will vary with the form of administration and the particular compound chosen, as well as with the particular host under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.

In general, the compounds of this invention are most desirably administered at a concentration dosage level which will generally afford effective results without causing any harmful side effects, and preferably at a level that is in a range of from about 5 mg. to about mg. per kilo body weight per day, although certain variations will occur as noted above. However, a dosage level in which the range is about 25 mg. to about 50 mg. per kilo body weight per day is most desirably employed in order to achieve effective results.

Furthermore, the 8,19-epoxysteroids of this invention possess antigonadotrophic activity. More particularly, the 8,19-epoxysteroids exhibit parenteral and oral activity when tested in standard pharmacological tests for antigonadotrophic activity such as, for example, the test described by C. Revesz and C. I. Chappel, J. Reprod. Fert., 12, 473 (1966). When the 8,19-epoxysteroids of this invention are used as antigonadotrophic agents, they may be employed as described above for their use as cholesterol lowering agents.

The 8,19-epoxysteroids of this invention may be conveniently prepared by a process schematically represented as follows:

| I. CH2

in which R and R together represent a ketonic oxygen or R represents hydrogen and R represents hydroxyl.

The starting materials of Formula II are 19-hydroxyandrosta-4,7-diene-3,l7-dione (II; R and R =0), described by G. Kruger, US. Pat. No. 3,325,519 and Netherlands Pat. No. 66/03491 and 17B,l9-dihydroxyandrosta- 4,7-dien-3-one (ll; R =H and R =OH-.

1713,19-dihydroxyandrosta-4,7-dien-3-one is readily prepared by reduction of 19-hydroxyandrosta-4,7-diene-3,17- dione with sodium borohydride.

Oxidation of the above two starting materials of Formula II with ferric chloride yields the corresponding 8,19-epoxysteroids of Formula I in which R and R are together a ketonic oxygen or R is hydrogen and R is hydroxyl, respectively. Satisfactory conditions for this oxidation include the use of 5l5 molar equivalents of ferric chloride ,a reaction time of 1-60 minutes, preferably 3-20 minutes; a temperature range of O to 40 C., preferably 15 to 25 C.; and the use of tetrahydrofuran, methanol, a mixture of tetrahydrofuran and methanol or ethyl acetate as solvent.

Alternatively, the conversion of the above starting materials of Formula II to the 8,19-epoxysteroids of Formula I in which R and R are together a ketonic oxygen or R is hydrogen and R is hydroxyl may be efiected by treating said starting materials with a N-haloacetamide or N- halosuccinimide, for example, N-bromoor N-chloroacetamide, or N-bromoor N-chlorosuccinirnide, in a solution of an aromatic base, preferably pyridine, to yield an intermediate 7-halo derivative of Formula II in which R and R are as defined in the last instance and X represents a halogen such as, for example, bromine or chlorine.This reaction is accomplished most effectively using temperatures ranging from to C. and a reaction period ranging from one to six hours. Subsequent treatment of the intermediate 7-halo derivative of Formula III with a proton acceptor, preferably pyridine, at elevated temperatures, preferably 80l15 C., for a period ranging from five minutes to six hours, preferably 10-30 minutes, affords the 8,19-epoxysteroids of Formula I in which R and R together represent ketonic oxygen or R is a hydrogen and R is hydroxyl.

The 17-lower acyl esters of 8,19-epoxy-17fi-hydroxyandrosta 4,6 dien 3 one (I; R =H and R OH), may be readily prepared by treating 8,19-epoxy-1713-hydroxyandrosta 4,6-dien-3-one, obtained by either of the above two processes, with the appropriate lower acyl anhydride or lower acyl halide in the presence of a proton acceptor, preferably pyridine.

In a related aspect of this invention, the 8,19-epoxysteroid I[R =H and R =OCO(CH may be obtained directly by utilizing the manipulative procedures for either of the two processes just discussed. In this case, 176,19- dihydroxyandrosta-4,7-dien-3-0ne 17-pivalate.

is used as starting material and is either treated as described above with ferric chloride or the two-step process involving treatment with a N-haloacetamide or N-halosuccinimide followed by treatment with an aromatic base. Said starting material is obtained by converting 65,19- epoxy-l7fl-hydroxyandrosta-4-en-3-one, described by K. Heusler, et al., Experientia, 18, 464 (1962), to its corresponding 17-pivalate by treatment with pivaloyl chloride or pivalic anhydride in pyridine solution, followed by treatment of the resulting pivalate -(IV, see below) with acetic anhydride and p-toluenesulfonic acid and subsequent treatment of the then obtained 19-acetate of 175, 19-dihydroxyandrosta-4,6-dien-3one pivalate under mild hydrolysis conditions to afford 17,8,l9-dihydroxyandrosta- 4,6-dien-3-one pivalate which may readily be converted to the corresponding A dien 3 ketosteroid, the said starting material, according to the condition used to convert A -3-ketosteroids to A -3-kct0steroids described by Kruger, cited above.

The 8,19-epoxysteroids of this invention may also be prepared by another process using 65,19-epoxy-17B-hydroxyandrost-4-en-3-one pivalate (IV) described above.

In this process the use of the pivalate ester, 6,8,19- epoxy 17fi-hydroxyandrost-4-en-3-one pivalate, serves a two-fold purpose. On the one hand, this ester group is retained by the intermediates in the process and yields directly the compound of Formula I in which R is hydrogen and R is the pivaloyloxy group. On the other hand, it serves as at protecting group for the 17 3-hydroxyl group during the process, allowing a final transformation to other 8,19-epoxysteroids of Formula I.

Regarding the use of the pivalate ester as a protecting group, it is apparent that other protecting groups may be used also, for example, the benzyl group or other such suitable groups described by F. N. McOmie, Protective 4 Groups, Advances in Organic Chemistry, 3, 216-251 (1963). The use of other suitable protecting groups is considered to be within the scope of the present invention.

This present process may be illustrated by the following formulae in which R represents hydrogen or lower acyloxy.

In practising this present process, 6{3,l9-epoxy-17-hydroxyandrost-4-en-3-one pivalate (IV) is treated with sulfuryl chloride and a proton acceptor, preferably collidine, with or without an inert solvent, for example, carbon tetrachloride, at an elevated temperature, preferably 40 to 80 C., to yield the 4-chloro derivative of Formula V. The latter compound is transformed to the A -3-ketone of Formula VI in which R represents a lower acyl group by treatment with lower acyl anhydride, for example, acetic anhydride, and an acid catalyst, for example, p-toluenesulfonic acid. The A -3-ketone of Formula VI in which R is a lower acyl group is then converted to the corresponding A -3-ketone of Formula VI in which R is a hydrogen by preferential hydrolysis, for example, under mild basic conditions such as employing an aqueous solution of potassium hydroxide, at room temperature.

When the A -3-ketone of Formula VI(R =H), thus obtained, is then subjected to the deconjugation conditions used to convert A -3-ketosteroids to corresponding A 3-ketosteroids, described by Kruger, cited above, the precipitate obtained on acidification of the reaction mixture is the corersponding 4-chloro-3,5,7-trien-3-ol of Formula VII and not the expected corresponding A -3-ketosteroid. It should be noted, however, that the 4-chloro-3,5,7-trien- 3-01 of Formula VII rearranges to 4-chloro-17fl,l9-dihydroxyandrosta-4,7-dien-3-one l7-pivalate on prolonged standing, for example, ten hours at room temperature in a nitrogen atmosphere. Hence it is desirable to effect the conversions described below for this compound of Formula VII as soon as possible after its isolation.

The unexpected isolation of the above 4-chloro3,5,7- trien-3-ol is the key step which allows the preparation of the 8,19-epoxysteroids of this invention by this present unique process. Accordingly, I have found that attempted acylation of the 4-chloro-3,5,7-trien-3-ol VII, isolated as described above, using an acyl anhydride, for example, acetic anhydride, in pyridine, readily yielded the corresponding 8,19-epoxy-l7/3-hydroxyandrosta-4,6-dien-3-one [1; R =H and R :OCOC(CH Subsequently it was found that the 4-chloro-3,5,7-trien- 3-ol (VII) may be conveniently and readily transformed into 8,19-epoxy-l-hydroxyandrosta-4.6-dicn-3-0ne by simple treatment with a basic aromatic solvent at temperature ranging from to 115 C. and using reaction times from one minute to 24 hours. Convenient reaction times and temperatures for this reaction are hours at room temperature or two hours at 80 C. and a preferred basic aromatic solvent is pyridine.

8,19-epoxy-175-hydroxyandrosta-4,6-dien3-one may be converted to the other 8,19-epoxysteroids of Formula I of this invention by the following methods:

1) Said compound may be hydrolyzed to yield the corresponding 175-o1 derivative, (1; R =H and R =OH) which may then be converted to the desired 17-lower acyl ester derivative of this invention by the acylation procedure, described above. Preferred conditions for this hydrolysis include heating 8,19-epoxy-175-hydroxyandrosta- 4,6-dien-3-one pivalate in 10% potassium hydroxide in aqueous methanol for hours.

(2) The 175-o1 derivative (I; R =H and R =OH), obtained by above method 1), may be oxidized to 8,19- epoxyandrosta-4,6-diene-3,17-dione by the usual methods for converting 175-o1 steroids to 17-ketosteroids, for example, see methods described by H. J. E. Loewenthal, Tetrahedron, 6, 295-299 (1959) or by C. Djerassi in Steroid Reactions, Holden-Day, Inc., San Francisco, 1963, pp. 89-154.

The following examples will further illustrate this invention.

EXAMPLE 1 To a solution of 19-hydroxyandrosta-4,7-diene-3,17- dione (1.0 g.), in 9.5 ml. of methanol and 0.5 ml. of pyridine, sodium borohydride (0.1 g.), is added. The reaction mixture is stirred for three minutes and then diluted with 60 ml. of water. The solid precipitate is collected, washed with water, dried, and recrystallized from methanol-water to yield 175,19 dihydroxyandrosta 4,7 dien-3-one as colorless crystals, M.P. 248-260 C.

EXAMPLE 2 A solution of 5.0 g. of 65,19-epoxy-175-hydroxyandrost- 4-en-3-one in 20 ml. of pyridine is heated with 7.5 ml. of pivaloyl chloride at 100 C. under nitrogen for two hours. The reaction mixture is diluted with 100 m1. of water and allowed to stand at room temperature for one hour during which time the supernantant oil crystallized. The crystals are collected, dried at 60 C. and recrystallized from ethanol to afford 65,19-epoxy-175-hydroxyandrost-4-en-3 one pivalate; M.P. l57-158 C.,

The latter compound (10.0 g.) mixed with 0.1 g. of ptoluenesulfonic acid and 3 ml. of acetic acid is heated at 100 C. for minutes whereupon 50 ml. of water is added at a slow rate. Extraction with methylene chloride, drying and evaporation yields the crude 19-acetate of 175,19-dihydroxyandrosta-4,6-dien 3 one 17 pivalate, which is dissolved in 10 ml. of methanol and left to stand at room temperature with 0.05 g. of sodium methoxide for 4 hours, whereupon 0.1 ml. of glacial acetic acid is added. Evaporation and recrystallization from methanol yields 175,19-dihydroxyandrosta-4,6 dien 3 one 17-pivalate; M.P. 191-192,

113 3460, 1715, 1650, 1615 and Example 3 To 19 hydroxyandrosta 4,7 diene 3,17 dione (5.0 g.) dissolved in 250 ml. of tetrahydrofuran-methanol (1:1) is added 20 g. of ferric chloride. The solution is stirred under nitrogen for 20 minutes whereupon 250 ml. of ethyl acetate and 750 ml. of water are added. The ethyl 1585 cmr 1740, 1665, 1619 and In the same manner, but using an equivalent amount of 175,19 dihydroxyandrosta 4,7 dien 3 one, prepared as described in Example 1, instead of 19 hydroxyandrosta 4,7 dien 3,17 dione, 8,19 epoxy 175 hydroxyandrosta-4,6-dien-3-one (I; R =H and R :OH), M.P. 169171 C., is obtained.

In the same manner, but using an equivalent amount of 175,19 -dihydroxyandrosta 4,7 dien 3 one 17- pivalate, prepared as described in Example 2, instead of 19 hydroxyandrosta 4,7 dien 3,17 dione, 8,19 epoxy 175 hydroxyandrosta 4,6 dien-3-one pivalate [1; R =H and R -=OCOC(CH M.P. 195.5196 C.,

Holt 1720, 1660, and 1615 CIIL-I To a solution of 19-hydroxyandrosta 4,7 diene-3,17- dione (3.0 g.) in 30 ml. of pyridine, N-bromoacetamide (1.3 g.) is added. The reaction mixture is allowed to stand at room temperature in the dark under a nitrogen atmosphere. After two hours, an additional amount (0.69 g.) of N-bromoacetamide is added. After the mixture has been allowed to stand for a total of 4 /2 hours, a solution of 300 ml. of 10% sodium bisulfite is added and the mixture is extracted with ether. The ether extract is washed twice with 300 ml. of 10% sodium bisulfite, then water, dried, and evaporated to dryness to give an oil. The oil is crystallized from ether to alford 7 bromo-8,19-epoxyandrost-4-ene-3,17-dione,

5 35 1732, 1670 and 1623 GEL-1 The latter compound (200 mg.) is dissolved in 0.5 ml. of pyridine and heated at C. for 25 minutes. The reaction mixture is cooled, diluted with hexane-ethyl acetate and water. The organic phase is separated, washed with water, dried and concentrated to yield a solid, which on crystallization from ethyl acetate gives a product identical with 8,19 epoxyandrosta 4,6 diene 3,17- dione, described in Example 3.

In the same manner, but using an equivalent amount of 175,19 dihydroxyandrosta 4,7 diene 3 one, prepared as described in Example 1, or its corresponding 17- pivalate, prepared as described in Example 2, instead of 19 hydroxyandrosta 4,7 diene 3,17 dione, 8,19- epoxy hydroxyandrosta 4,6 dien 3 one or its corresponding l7-pivalate, described in Example 3, are obtained respectively. In each case, the intermediates, 7 bromo 8,19 epoxy 175 hydroxyandrost-4-en-3- one or its corresponding 17-pivalate, may be isolated.

Example 5 Using the procedure described in Example 2 for the preparation of 65,19 epoxy 175 hydr0xyandrost-4- en 3 one 17 pivalate, but using an equivalent amount of 8,19 epoxy 175 hydroxyandrosta 4,6 dien-3-one, described in Examples 3 and 4, instead of 65,19-epoxy- 175-hydroxyandrost 4 en 3 one, and using an equivalent amount of acetic anhydride, propionic anhydride or butyric anhydride instead of pivaloyl chloride, 8,19- epoxy 175 hydroxyandrosta 4,6 diene 3 one acetate, 8,19 epoxy 175 hydroxyandrosta 4,6 dien- 3-one propionate and 8,19-epoxy 175 hydroxyandrosta- 4,6 dien 3 one butyrate are obtained, respectively.

Example 6 To a solution of 66,19 epoxy 17 8 hydroxyandrost- 4-en-3-one pivalate (IV, 8.0 g.) in 16 ml. of carbon tetrachloride and 8 ml. of sym.-collidine at 50 C., a solution of 16 ml. of redistilled sulfury chloride in 32 ml. of carbon tetrachloride is added over a period of 4 minutes.

Stirring is continued for another 8 minutes whereupon the mixture is poured into 48 ml. of methylene chloride and 48 ml. of 2 N aqueous hydrochloric acid. The organic phase is extracted four times with aqueous hydrochloric acid and then with water. Concentration of this phase to a thick paste and filtration yields off-white crystals. Recrystallization from methanol gives 4-chloro-6fi,19-epoxy- 17B hydroxyandrost 4 en 3 one pivalate (V), M.P. 212-214 C.,

max.

Example 7 A solution of 4-chloro 6,19 epoxy 175 hydroxyandrost-4-en-3-one (V, 3.0 g.), prepared as described in Example 6, and p-toluenesulfonic acid (3.0 g.) in ml. of acetic anhydride is allowed to stand at 100 under nitrogen for 10 minutes whereupon it is poured into 150 ml. of water and stirred for one hour. The aqueous phase is decanted from the viscous resin, the resin is dissolved in benzene and the solution stirred under nitrogen with one volume of 50% aqueous potassium hydroxide for 4 hours to destroy residual amounts of acetic anhydride. The benzene phase is dried (sodium sulfate) and evaporated at reduced pressure. The residue, consisting largely of 19-acetate (VI; R =COCH is dissolved in 30 ml. of methanol and left to stand with 0.3 ml. of 50% aqueous potassium hydroxide under nitrogen for one hour whereupon 0.3 ml. of glacial acetic acid is added and the mixture concentrated to a thick paste. The paste is filtered yielding off-white crystals, which after recrystallization from methanol give 4-chloro 176,19 dihydroxyandrosta 4,6 dien-3-one 17-pivalate (VI; R -H), M.P. 232-233 C.,

A553? 298 m (e=26,700) and 1615 cm.-

Example 8 To a solution of 4-chloro 1713,19 dihydroxyandrosta- 4,6-dien 3 one 17-pivalate (VI; R =H, 500 mg), prepared as described in Example 7, in 5 ml. of dimethylsulfoxide is added to 1.0 g. of sodium methoxide in one portion. The mixture is stirred briefly under nitrogen and then poured into 30 ml. of ice-cold 2 N-hydrochloric acid with stirring. The solid precipitate is collected immediately on a filter and dried in high vacuum at room temperature for 20 minutes yielding 4-chloroandrosta- 3,5,7-triene-3,175,19-triol 17-pivalate (VII),

N 305 (shoulder) 318 (major maximum) and 333 my. (shoulder). On standing in a nitrogen atmosphere for 10 hours the latter product rearranges to 4 chloro 1713,19 dihydroxyandrosta-4,7-dien-3-one 17-pivalate,

rmor! 255 m Treatment of 4-chloroandrosta 3,5,7 triene-3, 17 9,19- triol l7-pivalate with acetic anhydride-pyridine (1:3) instead of pyridine gives the identical product.

Example 9 A solution of 8,19 epoxy 17B hydroxyandrosta- 4,6-dien-3-one pivalate (1.0 g.), described in Examples 3, 4 and 8, in ml. of 10% methanolic potassium hydroxide solution containing 0.5 ml. of water is boiled under nitrogen for 20 hours. The reaction mixture is concentrated and diluted with water. The solid is collected, washed with water, dried and recrystallized from ethyl acetate to yield a product identical to 8,19-epoxy-17B- hydroxyandrosta-4,6-dien-3-one, described in Examples 3 and 4.

Example 10 8,9 epoxy 17,8 hydroxyandrosta 4,6 dien-3-one (I; R =H and R =OH) may be converted to 8,19-epoxyandrosta-4,6-dien-3,17-dione (I; R and R =O) by a variety of oxidizing procedures, see Loewenthal or Djerassi, cited above.

For instance, by dissolving 0.72 g. of 8,19-epoxy-17fi hydroxyandrosta-4,6dien-3-one in 25 ml. of acetic acid and one ml. of water, and treating dropwise the resulting solution with 0.23 g. of chromium trioxide in 2 ml. of water at room temperature, then allowing the reaction mixture to stand for two hours, followed by the addition of ethanol to decompose excess reagent, and then adding water produces a solid precipitate which may be collected, washed with water and recrystallized from ethyl acetate to afford a product identical with 8,19-epoxyandrosta-4,6- diene-3,17-dione, described in Examples 3 and 4.

I claim:

1. A compound of the formula in which R and R together represent a -ketonic oxygen, or R represents hydrogen and R is selected from the group which consists of hydroxyl and lower acyloxy.

2. 8,19 epoxyandrosta 4,6 diene 3,17 dione, as claimed in claim 1.

3. 8,19 epoxy 17,6 hydroxyandrosta 4,6 dien-3- one, as claimed in claim 1.

4. 8,19 epoxy 17,8 -hydroxyandrosta 4,6 dien-3- one-pivalate, as claimed in claim 1.

5. 4 chloro 65,19 epoxy 17B hydroxyandrost-4- en-3-one-pivalate.

6. 4 chloro 175,19 dihydroxyandrosta 4,6 dien- 3-one 17-pivalate.

7. 4 chloroandrosta 3,5,7 triene 3,175,19 triol 17-pivalate.

8. The process of preparing a compound of the formula R1 cny j l L I wherein R and R together represent a ketonic oxygen, or R represents hydrogen and R is selected from the group which consists of hydroxyl and lower acyloxy, which comprises treating a compound of the formula wherein R and R together represent a ketonic oxygen, or R represents hydrogen and R represents hydroxyl, with a molar excess of ferric chloride.

9. The process of preparing a compound of the formula wherein R and R together represent a ketonic oxygen, or R represents hydrogen and R is selected from the group which consists of hydroxyl and lower acyloxy, which comprises treating a compound of the formula wherein R and R together represents a ketonic oxygen, or R represents hydrogen, and R represents hydroxyl, with a reagent selected from the group which consists of N-hal0acetamides and N-halosuccinimides, thereby obtaining a compound of the formula wherein R and R together represent a ketonic oxygen, or R represents hydrogen and R represents hydroxyl, and X represents a halogen: and treating said last named compound with a proton acceptor, thereby obtaining said desired compound.

10. The process of preparing a compound of the formula R1 \l/ CH2 I wherein R i hydrogen and R is the pivaloyloxy group which comprises treating 6,8,19-epoxy-17,8-hydroxyandrost- 4-en-3-one pivalate with sulfuryl chloride and a proton acceptor to obtain 4-chloro-6B,19-epoxy 17B hydroxyandrost-4-en-3-one pivalate; treating said last-named compound with a lower acyl anhydride in the presence of an acid catalyst, thereby obtaining the corresponding 19- acylate of 4-ch1oro-17B,19-dihydroxyandrosta-4,6-dien-3- one 17-piva1ate; treating said last-named compound with a base to obtain 4-chloro-17;3,19-dihydroxyandrosta-4,6- dien-3-one 17-pivalate; treating said last-named compound with a strong base following by treatment with a strong acid, thereby obtaining 4-chloroandrosta-3,5,7-triene-3, 17,3,19-triol 17-pivalate; and treating said last-named compound with a basic aromatic solvent, thereby obtaining the desired compound.

No references cited.

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

P0405) UNITED STATES PATENT OFFICE 69) CERTIFICATE OF CORRECTION Patent N6. 3 637,667 Dated J ggary 25. 1972 Inventor(s) Gunther Kruger It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 4, first formula, "V'I should read IV Column 4, formula V "Cl" should be inserted in position 4 so that formula should read OCOC(CH3)3 Column 4, formula VI, "0R Should read 0R Column 4, formula VII, the double bond in position 7,8 should be inserted.

Column 4, line 33, "6B,l9-epoxy-l7-hydroxyandrost" should read 6B,l9-epoxy-l7l -hydroxyandrost 32 3 6 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3.637.667 Dated Inventor s) Gunther Kruger It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 8, line 18, "8,9-epoxy" should read 8,19-Epoxy Column 9, first formula, "-CH =OH" should read -CH -OH Signed and sealed this 5th day of September 1972.

(SEAL) Attest:

ROBERT GOTTSCHALK EDWARD FLFLETGHEKJR.

Commissioner of Patents Attesting Officer 

